Aminoalkyl-benzofuran-5-ol compounds for the treatment of glaucoma

ABSTRACT

The present invention provides novel compounds, compositions containing the compounds of the invention in a pharmaceutically acceptable excipient and methods for using the compositions for lowering intraocular pressure.

This application claims benefit of Provisional Application Ser. No.60/340,361, filed Dec. 14, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to treatment for lowering intraocularpressure and to compounds for use in such treatments. More particularly,the present invention relates to the use of compounds with serotonergic5-HT5-HT₂ agonist activity to lower intraocular pressure (IOP), treatglaucoma, and to provide neuroprotection.

2. Description of the Related Art

Serotonin (5-hydroxy tryptamine; 5-HT5-HT) is an endogenous biogenicamine with a well defined neurotransmitter function in many tissues ofthe body including the eye [Zifa and Fillion 1992; Hoyer et al. 1994;Tobin et al. 1988].

5-HT is known to interact with at least seven major 5-HT receptors(5-HT₁–5-HT₇) and additional subtypes within these families to initiateintracellular biochemical events such as stimulation of secondmessengers (e.g. cAMP, inositol trisphosphate) eventually leading to thefinal biological response, for example, tissue contraction or hormonerelease, etc. [Hoyer et al. 1994; Martin et al. 1998]. Receptor subtypeswithin the 5-HT₁ family are negatively coupled to adenylyl cyclase (AC)and cause inhibition of cAMP production, while 5-HT₄, 5-HT₆, and 5-HT₇receptors are positively coupled to AC and thus stimulate cAMPproduction when activated by 5-HT [Martin et al. 1998]. The receptors inthe 5-HT₂ family are positively coupled to phospholipase C (PLC) andthus generate inositol phosphates and mobilize intracellular calciumwhen activated to mediate the effects of 5-HT. The 5-HT₃ receptor isunique in that it couples to an ion channel which gates sodium,potassium, and calcium [Hoyer et al. 1994].

The human and animal 5-HT₇ receptor has only recently been cloned,expressed, and shown to be present in various brain areas and peripheraltissues [Eglen et al. 1997]. Recent studies have shown there to be foursplice variants of the 5-HT₇ receptor [Heidmann et al. 1997]. It hasbeen proposed that the 5-HT₇ receptor may be involved in thepathophysiology of sleep disorders, depression, and other psychiatricdisorders [Eglen et al. 1997]. In the periphery, stimulation of 5-HT₇receptors results in relaxation of blood vessels and hence vasodilation[Eglen et al. 1997].

Known compounds exhibiting 5-HT₂ agonist activity have typically beendesigned to treat numerous central nervous system (CNS)-relatedconditions, particularly the treatment of obesity and depression, byactivation of 5-HT_(2C) receptors. Thus, one desired property of known5-HT₂ agonist compounds is that they easily penetrate the blood brainbarrier. Compounds possessing the property of penetration into the CNSgenerally do not contain polar groups.

To treat ocular diseases, it is desirable to administer compositionsorally or topically that will remain in the ocular tissues and not crossthe blood brain barrier to enter the CNS. What are needed are 5-HT₂agonist compounds that are useful in the treatment of ocular diseasescharacterized by an elevated intraocular pressure, the treatment ofglaucoma and neuroprotection. Such compounds would not have a propensityto cross the blood brain barrier.

SUMMARY OF THE INVENTION

The present invention overcomes these and other drawbacks of the priorart by providing compounds having 5-HT₂ agonist activity that do notcross the blood brain barrier. More specifically, the present inventionprovides compounds having the following general formula:

wherein R¹ is hydrogen or C₁₋₄alkyl; R² is hydrogen, C₁₋₄alkyl, or R¹and R² can together be (CH₂)₂₋₄ to complete a heterocyclic ring; R³ ishydrogen, hydroxyl, C₁₋₄alkoxy, or fluorine; R⁴ is selected fromC₁₋₄alkyl, halogen, nitrile, C₁₋₆alkylthiol, trifluoromethyl, C₁₋₄alkylsubstituted by HO or C₁₋₃alkoxy, R⁵ is hydrogen, halogen, C₁₋₄alkoxy,nitrile, W is hydrogen or C(═O)C₁₋₈alkyl. In preferred embodiments, R¹,R³ and R⁵ are hydrogen, R² is methyl, R⁴ is halogen, methyl ortrifluoromethyl, and W is hydrogen. Most preferably, the compounds ofthe invention have an R-configuration at the carbon atom bearing theprimary amine.

In another aspect, the present invention provides compositionscontaining the compounds described above in a pharmaceuticallyacceptable excipient. The compositions are most preferably in the formof topical ophthalmic formulations for delivery to the eye. Thecompounds of the invention may be combined with ophthalmologicallyacceptable preservatives, surfactants, viscosity enhancers, penetrationenhancers, buffers, sodium chloride, and water to form an aqueous,sterile ophthalmic suspension or solution to form the compositions ofthe invention.

The compositions of the invention are preferably formulated as topicalophthalmic suspensions or solutions, with a pH of about 5 to 8. Thecompounds of the invention as described above will normally be containedin these formulations in an amount 0.01% to 5% by weight, but preferablyin an amount of 0.25% to 2% by weight. Thus, for topical presentation 1to 2 drops of these formulations would be delivered to the surface ofthe eye 1 to 4 times per day according to the routine discretion of askilled clinician.

The present invention further provides a method of lowering intraocularpressure in a mammal by administering to a patient in need thereof atherapeutically effective amount of a composition comprising a compoundhaving the structure as described above in a pharmaceutically acceptableexcipient. In preferred embodiments, the composition can be administeredsystemically or locally to the eye (e.g., topically, intracamerally, orvia an implant).

DETAILED DESCRIPTION PREFERRED EMBODIMENTS

It has been found that serotonergic compounds which possess agonistactivity at 5-HT₂ receptors effectively lower and control elevated IOPand glaucoma. Serotonergic nerves innervate the eye [Tobin et al. 1988]and 5-HT has been found in the aqueous humor of human eyes [Martin etal. 1988]. In addition, receptor binding sites for [³H]5-HT have beendemonstrated and pharmacologically characterized in the iris-ciliarybody (ICB) of rabbits [Mallorga and Sugrue 1987; Chidlow et al. 1995].These 5-HT binding sites have been shown to be functionally coupled tosecond messenger generation in rabbits [Tobin and Osborne 1989; Tobin etal. 1988]. In the human ICB these binding sites are characterized as5-HT_(1A) and 5-HT₂ receptors [Barnet and Osborne 1993]. In addition,the presence of mRNAs for 5-HT_(1A) and 5-HT₇ receptors in the rabbitICB have been reported [Chidlow et al. 1995; Osborne and Chidlow 1996].The precise functions of these receptors in the eye are unknown,especially the 5-HT₇ subtype(s).

5-HT or 5-carboxamidotryptainine (5-CT) topically applied to the rabbiteye raise intraocular pressure in the anterior chamber of the eye[Meyer-Bothling et al. 1993]. By contrast, it has been shown thattopically applied 5-HT lowers IOP [Krootila et al. 1987 (intracamerally5-HT raised IOP and caused breakdown of the blood-aqueous barrier)]. Inaddition, the 5-HT uptake inhibitor, fluoxetine (Prozac®), also raisesIOP in human subjects upon oral administration [Costagliola et al. 1996]and may cause glaucoma [Ahmad 1992]. However, the 5-HT receptorsubtype(s) involved in the IOP-elevating effects of 5-HT, 5-CT andfluoxetine are unknown.

Studies conducted in rabbits with 8-hydroxy DPAT and MKC-242 (5-HT_(1A)agonists) have shown these compounds lower IOP [Osborne and Chidlow1996; EP 0771563-A2]. In addition, 5-methylurapidil (5-HT_(1A) agonist)lowered IOP in glaucomatous monkeys [Wang et al. 1997]. Both MKC-242 and5-methylurapidil are relatively potent α1 receptor antagonists (α1antagonists are known to lower IOP in rabbits, monkeys, and man). Themechanism of action for lowering IOP by 5-methylurapidil has beenattributed to its α1 antagonist activity and not its 5-HT_(1A) agonistactivity [Wang et al. 1998]. U.S. Pat. No. 5,693,654, discloses 5-HT₁receptor agonists for lowering IOP. WO 92/20333 discloses certain5-HT_(1A) agonists for the treatment of glaucoma.

Methysergide (5-HT₂ antagonist) lowered IOP in rabbits [Krootila et al.1987]. Ketanserin (5-HT_(2A/C) antagonist), also with significant α1antagonist activity, lowers IOP in rabbits and man [Chan et al. 1985;Costagliola et al. 1991]. Saprogrelate (5-HT_(2A) antagonist) lowers IOPin rabbits and in man when dosed topically or orally [Mano et al. 1995;Takenaka et al. 1995]. EP 522226 and U.S. Pat. No. 5,290,781 disclosethe use of ketanserin and its derivatives for treating ocularhypertension. U.S. Pat. Nos. 5,290,781 and 5,106,555 discloses the useof certain 5-HT₂ antagonists for lowering, IOP. U.S. Pat. No. 5,652,272discloses saprogrelate for reducing IOP. U.S. Pat. No. 5,538,974discloses opthalmic compositions of certain 5-HT₂ antagonists forlowering IOP.

U.S. Pat. No. 5,011,846 discloses certain 5-HT₃ receptor antagonists fortreating glaucoma.

WO 97/17345 discloses that particular compounds with 5-HT₄ serotonergicreceptor agonist or antagonist activity are useful for treatingpsychiatric, gastrointestinal, lower urinary, and cardiovasculardisorders. The publication mentions the compounds may also be useful forglaucoma.

The present inventor has discovered that compounds with the generalformula (I) have 5-HT₂ agonist activity and may be useful in loweringIOP, treating glaucoma, and/or provide neuroprotection for retinalganglion cells.

In Formula I, R¹ is hydrogen or C₁₋₄ alkyl; R² is hydrogen, C₁₋₄alkyl,or R¹ and R² together can be (CH₂)₂₋₄ to complete a heterocyclic ring;R³ is hydrogen, hydroxyl, C₁₋₄alkoxy, or fluorine; R⁴ is selected fromC₁₋₄alkyl, halogen, nitrile, C₁₋₆alkylthiol, trifluoromethyl, C₁₋₄alkylsubstituted by HO or C₁₋₃alkoxy, R⁵ is hydrogen, halogen, C₁₋₄alkoxy,nitrile and W is hydrogen or C(═O)C₁₋₈alkyl.

The compounds of the invention will preferably possess the followingproperties: 1) agonist acitivty at the 5-HT₂ receptors, and 2)significantly greater chemical stability than serotonin, the endogenousreceptor ligand.

D. E. Nichols and colleagues at Purdue University have developed anumber of benzofuran- and benzodifuranyl-alkylamines over the pastdecade and have demonstrated their affinity and efficacy at the5-HT_(2A) receptor as well as their hallucinogenic activity as evaluatedin animals. Dr. Nichols' focus has been on the development of compoundswith CNS activity, that is, that readily cross the blood brain barrier.Thus, these known compounds are outside of the scope of the compoundsencompassed by Formula I above.

For example, Nichols has developed a compound with the followingstructure (compound 1) (Parker et al. 1998).

Compound I

The Nichols compound has been shown to have a high affinity for the5-HT_(2A) receptor and to generalize to LSD in drug discriminationstudies. Nichols and colleagues also studied compounds in the class ofthat shown below (compound 2) for CNS activity.

(Monte et al. 1996). Neither of the compounds studied by Nichols andcolleagues is within the scope of the present invention. Furthermore,Nichols does not discuss use of compounds 1 or 2 for the treatment ofany ocular diseases, ocular hypertension or glaucoma. The goal increating compounds 1 and 2 was to produce compounds useful for CNSdisorders and such compounds would necessarily have to have the abilityto penetrate the blood brain barrier. In contrast, the compounds of thepresent invention are designed not to cross the blood brain barrier butto remain in the ocular tissue.

Eli Lilly developed a series of benzofuran compounds that are similar tothe compounds of Formula I herein. (WO 00/44737). Lilly's compounds havethe following general formula:

These compounds are described as having utility for numerous CNS-relatedconditions, particularly the treatment of obesity and depression byactivation of 5-HT_(2C) receptors. Thus, it is desirable that thesecompounds would penetrate into the brain. None of the compoundsdescribed in Lilly come within scope of the present invention. Thecompounds of the invention are designed to avoid penetration into thebrain whereas the Lilly compounds are specifically aimed at crossing theblood brain barrier in order to treat CNS diseases.

The compounds of the invention have a low propensity to enter the CNS,or to cross the blood brain barrier, due to the presence of the highlypolar hydroxyl group. Thus, the compounds of the invention are lesslikely to elicit undesirable centrally mediated side effects, such asthose associated with the CNS active compounds described by Nichols andLilly. The preferred 4-substituted 7-(2-aminopropyl)-benzofuran-5-olcompounds of Formula I have a greater chemical stability than serotoninor other indole analogs.

The compounds of the invention may be prepared by known syntheticprocedures, such as those reported in WO 00/44737, and other well knownsynthetic transformations.

The compounds of the invention can be administered systemically orlocally to the eye (e.g., topically, intracamerally, or via an implant).The compounds are preferrably incorporated into topical ophthalmicformulations for delivery to the eye. The compounds may be combined withophthalmologically acceptable preservatives, surfactants, viscosityenhancers, penetration enhancers, buffers, sodium chloride, and water toform an aqueous, sterile ophthalmic suspension or solution. Ophthalmicsolution formulations may be prepared by dissolving a compound in aphysiologically acceptable isotonic aqueous buffer. Further, theophthalmic solution may include an ophthalmologically acceptable issurfactant to assist in dissolving the compound. Additionally, theophthalmic solution may contain an agent to increase viscosity, such as,hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, orthe like, to improve the retention of the formulation in theconjunctival sac. Gelling agents can also be used, including, but notlimited to, gellan and xanthan gum. In order to prepare sterileophthalmic ointment formulations, the active ingredient is combined witha preservative in an appropriate vehicle, such as, mineral oil, liquidlanolin, or white petrolatum. Sterile ophthalmic gel formulations may beprepared by suspending the active ingredient in a hydrophilic baseprepared from the combination of, for example, carbopol-940, or thelike, according to the published formulations for analogous ophthalmicpreparations; preservatives and tonicity agents can be incorporated.

The compounds of the invention are preferably formulated as topicalophthalmic suspensions or solutions, with a pH of about 5 to 8. Thecompounds will normally be contained in these formulations in an amount0.01% to 5% by weight, but preferably in an amount of 0.25% to 2% byweight. Thus, for topical presentation 1 to 2 drops of theseformulations would be delivered to the surface of the eye 1 to 4 timesper day according to the routine discretion of a skilled clinician.

The compounds can also be used in combination with other IOP loweringagents, such as, but not limited to, β-blockers, prostaglandins,carbonic anhydrase inhibitors, area α-₂ agonists and miotics. Thecompounds can also be used in combination with other agents useful fortreating glaucoma, such as, but not limited to, calcium channel blockersand NMDA antagonists. These agents may be administered topically, butusually systemically.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically and structurallyrelated may be substituted for the agents described herein to achievesimilar results. All such substitutions and modifications apparent tothose skilled in the art are deemed to be within the spirit, scope andconcept of the invention as defined by the appended claims.

References

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

U.S. Pat. Nos. 5,011,846 5,106,555 5,290,781 5,538,974 5,652,2725,693,654

Foreign Patents and Published Applications

EP 0771563-A2

EP 522226

WO 92/20333

WO 97/17345

Other Publications

-   Ahmad, Ann. Pharmacother., 25:436, 1992.-   Barnet and Osborne, Exp. Eye Res., 57:209–216, 1993.-   Chan et al., J. Ocular Pharmacol., 1:137–147, 1985.-   Chidlow et al., Invest. Ophthalmol. Vis. Sci., 36:2238–2245, 1995.-   Costagliola et al., Br. J. Ophthalmol., 80:678, 1996.-   Costagliola et al., Ex. Eye Res., 52:507–510, 1991.-   Eglen et al., Trend Pharmacol. Sci., 18:104–107, 1997.-   Heidmann et al., J. Neurochem., 68:1372–1381, 1997.-   Hoyer et al., Pharmacol. Rev., 46:157–203, 1994.-   Krootila et al., J. Ocular Pharmacol., 3:279–290, 1987.-   Mallorga and Sugrue, Curr. Eye Res., 6:527–532, 1987.-   Mano et al., Invest. Ophthal. Vis. Sci., 36(Suppl):3322–309, 1995.-   Martin et al., Ophthalmol., 95:1221–1226, 1988.-   Martin et al., Trends Pharmacol. Sci., 19:2–4, 1998.-   Meyer-Bothling et al., Invest. Ophthalmol. Vis. Sci., 34:3035–3042,    1993.-   Osborne and Chidlow, Ophthalmologica, 210:308–314, 1996.-   Takenaka et al., Invest Ophthal. Vis. Sci., 36(Suppl):3390–377,    1995.-   Tobin et al., J. Neurosci., 8:3713–3721, 1988.-   Tobin and Osborne, J. Neurochem., 53:686–601, 1989.-   Wang et al., Curr. Eye Res., 16:679–775, 1997.-   Wang et al., Invest. Ophthal. Vis. Sci., 39(Suppl):2236–488, 1998.-   Zifa and Fillion, Pharmacol. Rev., 44:401–458, 1992.

1. A compound having the structure as follows:

wherein R¹ is hydrogen or C₁₋₄alkyl; R² is hydrogen, C₁₋₄alkyl, or R¹and R² can together be (CH₂)₂₋₄ to complete a heterocyclic ring; R³ ishydrogen, hydroxyl, C₁₋₄alkoxy, or fluorine; R⁴ is selected fromC₁₋₄alkyl, halogen, nitrile, C₁₋₆alkylthiol, trifluoromethyl, C₁₋₄alkylsubstituted by HO or C₁₋₃alkoxy, R⁵ is hydrogen, halogen, C₁₋₄alkoxy,nitrile, W is hydrogen or C(═O)C₁₋₈alkyl.
 2. The compound of claim 1,wherein R¹, R³ and R⁵ are hydrogen, R² is methyl, R⁴ is halogen, methylor trifluoromethyl, C₁₋₄alkyl substituted by HO or C₁₋₃alkoxy, and W ishydrogen.
 3. The compound of claim 2, further defined as thestereoisomer with an R-configuration at the carbon atom bearing theprimary amine.
 4. A composition comprising at least one compound havingthe structure as follows and a pharmaceutically acceptable excipient:

wherein R¹ is hydrogen or C₁₋₄alkyl; R² is hydrogen, C₁₋₄alkyl, or R¹and R² can together be (CH₂)₂₋₄ to complete a heterocyclic ring; R³ ishydrogen, hydroxyl, C₁₋₄alkylthiol, or fluorine; R⁴ is selected fromC₁₋₄alkyl, halogen, nitrile, C₁₋₆alkylthiol, trifluoromethyl, C₁₋₄alkylsubstituted by HO or C₁₋₃alkoxy, R⁵ is hydrogen, halogen, C₁₋₄alkoxy,nitrile, W is hydrogen or C(═O )C₁₋₈alkyl.
 5. The composition of claim4, wherein the compound is further defined as follows: R¹, R³ and R⁵ arehydrogen, R² is methyl, R⁴ is halogen, methyl or trifluoromethyl,C₁₋₄alkyl substituted by HO or C₁₋₃alkoxy, and W is hydrogen.
 6. Thecomposition of claim 5, wherein the compound is further defined as thestereoisomer with an R-configuration at the carbon atom bearing theprimary amine.
 7. The composition of claim 4, further comprising anophthalmologically acceptable preservative.
 8. The composition of claim4, further comprising an ophthalmologically acceptable surfactant. 9.The composition of claim 4, further comprising an agent selected fromthe group consisting of hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, and polyvinylpyrrolidone.10. The composition of claim 4, further defined as a topical ophthalmicsuspension or solution having a pH of about 5 to about
 8. 11. Thecomposition of claim 10, wherein the concentration of the compound isfrom 0.01% to 5% by weight.
 12. The composition of claim 11, wherein thecomposition of the compound is from 0.25% to 2% by weight.
 13. A methodof lowering intraocular pressure in a mammal, said method comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a composition comprising a compound having the structure asfollows:

wherein R¹ is hydrogen or C₁₋₄alkyl; R² is hydrogen, C₁₋₄alkyl, or R¹and R² can together be (CH₂)₂₋₄ to complete a heterocyclic ring; R³ ishydrogen, hydroxyl, C₁₋₄alkoxy, or fluorine; R⁴ is selected fromC₁₋₄alkyl, halogen, nitrile, C₁₋₆alkylthiol, trifluoromethyl, C₁₋₄alkylsubstituted by HO or C₁₋₃alkoxy, R⁵ is hydrogen, halogen, C₁₋₄alkoxy,nitrile, W is hydrogen or C(═O)C₁₋₈alkyl.
 14. The method of claim 13,wherein R^(1,) R³ and R⁵ are hydrogen, R² is methyl, R⁴ is halogen,methyl or trifluoromethyl, C₁₋₄alkyl substituted by HO or C₁₋₃alkoxy,and W is hydrogen.
 15. The method of claim 14, wherein the compound isfurther defined as the diastereomer with an R-configuration at thecarbon atom bearing the primary amine.
 16. The method of claim 13,wherein the composition is in the form of a topical ophthalmicsuspension or solution.
 17. The method of claim 13, wherein thecomposition is administered by topical application to the eye.